Practical Heck-Mizoroki coupling protocol for challenging substrates mediated by an N-heterocyclic carbene-ligated palladacycle

Article abstract of DOI:10.1021/ol8012809

(Chemical Equation Presented) A highly active, N-heterocyclic carbene-palladacycle precatalyst for the Heck-Mizoroki reaction was rationally designed. The complex can be synthesized on a large scale in excellent yield by a novel, one-pot, three-component reaction and is tolerant to air, moisture, and long-term storage. A wide range of challenging substrates is successfully coupled under a simple and user-friendly reaction protocol.

Full text of DOI:10.1021/ol8012809

ORGANIC
LETTERS
2008
Vol. 10, No. 18
3949-3952
Practical Heck-Mizoroki Coupling
Protocol for Challenging Substrates
Mediated by an N-Heterocyclic
Carbene-Ligated Palladacycle
Eric Assen B. Kantchev, Guang-Rong Peh, Chi Zhang, and Jackie Y. Ying*
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
Singapore 138669, Singapore
jyying@ibn.a-star.edu.sg
Received June 6, 2008
ABSTRACT
A highly active, N-heterocyclic carbene-palladacycle precatalyst for the Heck-Mizoroki reaction was rationally designed. The complex can be
synthesized on a large scale in excellent yield by a novel, one-pot, three-component reaction and is tolerant to air, moisture, and long-term
storage. A wide range of challenging substrates is successfully coupled under a simple and user-friendly reaction protocol.
The development of novel catalysts with improved perfor-
mance for Pd-mediated cross-coupling reactions underpins
the broad range of applications of cross-coupling reactions
in organic synthesis.1 The Heck-Mizoroki reaction2 has
become one of the most widely employed within this family
of transformations for the assembly of complex molecules.3
While coupling of simple aryl iodides or bromides can be
achieved in high yields with virtually any Pd source,4 cross-
coupling of functionalized aryl and heteroaryl substrates such
as those found in drug molecules poses significant chal-
lenges5 and requires the addition of a spectator ligand that
modifies the steric and electronic properties of the Pd center.
In recent years, two families of highly active, broadly
applicable classes of ligands have emerged: phosphanes1,6
and N-heterocyclic carbenes (NHCs).7 Wide adoption of
catalytic protocols is facilitated when availability, cost,
(1) Metal-catalyzed cross-coupling reactions, 2nd ed.; De Meijere, A.,
Diederich, F., Eds.; John Wiley & Sons: New York, 2004.
(2) (a) Bra¨se, S.; De Meijere, A. Metal-catalyzed cross-coupling
reactions, 2nd ed.; De Meijere, A., Diederich, F., Eds.; Weinheim, 2004;
Vol. 1, p 217. (b) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000,
100, 3009.
(3) Review: Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem.,
Int. Ed. 2005, 44, 4442.
(4) Review: Farina, V. AdV. Synth. Catal. 2004, 346, 1553.
10.1021/ol8012809 CCC: $40.75
Published on Web 08/19/2008
2008 American Chemical Society

stability, tolerance to impurities, oxygen and moisture,
avoidance of highly toxic and difficult to remove reagents,
as well as ease of usage are taken into consideration, in
addition to the intrinsic activity of the catalyst. Herein, we
present such a totally designed Heck-Mizoroki protocol for
the coupling of challenging aryl bromides and iodides based
on a novel NHC-ligated palladacycle.
Under cross-coupling conditions, palladacycles are shown
to decompose with the liberation of catalytically active,
ligandless palladium.8 Even though Pd complexes of a bulky
carbene, 1,3-dimesitylimidazolyl-2-ylidene (IMes), have been
shown to catalyze Heck-type coupling of simple aryl
bromides or aryl diazonium salts with acrylates or styrene,9
more complex, functionalized substrates have received little
attention. Therefore, we reasoned that the hitherto unknown10
complex (3, Scheme 1, Figure 1) of IMes and o-palladated
yielding NHC-palladacycle synthesis that would employ
stable NHC precursors (imidazolium salts) and in situ
prepared palladacycles without the need for anhydrous
techniques or a glovebox. Heating PdCl2 and the com-
mercially available, inexpensive amine 2 in HPLC-grade
acetonitrile in air in the presence of excess K2CO3 followed
by the addition of commercial NHC precursor IMes·HCl (1)
led to near quantitative yield of complex 3. Under optimized
conditions, a large quantity of 3 (95 g; 90% yield) was
obtained after simple crystallization. The initial assessment
of the catalytic activity of 3 (Table 1) was conducted at
Table 1. Initial Assessment of the Catalytic Activity of 3a
Scheme 1
.
Optimized, One-Pot, Three-Component Synthesis of
a NHC-Palladacycle
entry
3 (mol %)
time (h)
6/4 (%)
TONb
1
2
3
4
5
6
2.0
0.10
0.010
1.0 × 10-3
1.0 × 10-4
1.0 × 10-5
18
24
72
72
168
168
100/0c
86/6.2
59/32
54/40
11/81
5.2/74
-
-
-
-
1.14 × 105
5.22 × 105
a The reactions (1.0 M of p-bromoanisole (4), 2.0 M of tert-butyl acrylate
(5)) were performed in duplicate. The average product yield and starting
material recovery ((4%) were determined by quantitative 1H NMR
spectroscopy (internal standard: N,N-dimethylformamide (DMF)). b TON
) mmol 6/mmol 3. c Isolated yield.
N,N-dimethylbenzylamine (dmba)11 would possess expanded
substrate scope, while maintaining high activity as a
catalyst loadings of 0.1-10-5 mol % with tert-butyl acrylate
(5) and a deactivated arylbromide, p-bromoanisole (4).
Notably, 54% of 6 was formed at 10 ppm of Pd, comparable
with the FDA-approved limit for Pd content in pharmaceu-
ticals. The catalyst attained a maximum turnover number
(TON) of 5.22 × 105 at a loading of 1.0 × 10-5 mol %.
More challenging aryl halides, such as those containing
two o-substituents (9, 15, 16; Scheme 2), free anilines (12,
19) or phenols (10, 11), and multiple methoxy groups
(19-22) coupled well over 2 mol % of 3. The protocol was
compatible with aryl chlorides (10) and benzyl-protected
phenols (13). The coupling of the heterocycle was sensitive
to the nature of the heterocyclic ring. Pyrimidine (17, 19),
pyridine (23, 24), or thiophene derivatives (18, 20) coupled
in good to excellent yields. Whereas the imidazole derivative
21 was obtained in 82% isolated yield, the challenging
bromopyrazole containing two o-methyl groups only coupled
in 32% yield (22)14 (4 mol % of 3; 49% of the starting
bromide was recovered). However, the presence of hetero-
cyclic rings further away from the reaction site was well
tolerated (16, 29). Among Heck acceptors, vinylferrocene
(8) and 4-vinylpyridine (24) were coupled for the first time
under NHC-Pd catalysis. Moreover, the catalyst could be
used in air without significant loss of activity in most cases.
Notably, by careful choice of base, we have achieved the
first Heck-Mizoroki couplings (Table 2) of diethyl vi-
Figure 1. ORTEP representation of the solid-state molecular
structure of complex 3. The thermal ellipsoids are shown at 30%
probability, and the hydrogen atoms are omitted for clarity.
Heck-Mizoroki precatalyst. However, the current methods
for NHC-palladacycle preparation require purified dimeric
palladacycles. The carbene ligands are then introduced via
µ-chloride displacement with isolated, highly moisture- and
air-sensitive NHCs.12 On the other hand, methods that use
moisture- and air-tolerant carbene surrogates have limited
scope and proceed only in low to moderate yields.13 To
address these shortcomings, we sought a practical, high-
3950
Org. Lett., Vol. 10, No. 18, 2008

Scheme 2
.
Heck-Mizoroki Couplings of Functionalized Aryl
Table 2. Heck-Mizoroki Couplings of Less Common Alkenes
Mediated by Complex 3a
and Heteroaryl Bromides and Iodides Mediated by Complex 3,
Showing Isolated Yields of Chromatographically Homogeneous
Materials, Average of Two Runs (NMP )
2-Methyl-1-pyrrolidone)a
entry conditions alkene
K2CO3,
R1
R2
yield (%)
1
2
3
4
100 °C
26
27
28
29
H
H
H
CN
88 (30)b
iPr2NEt,
120 °Cc
NaOAc,
120 °Cc
NaHCO3,
120 °C
PO(OEt)2 61 (31)
SO2Ph
37 (32)
-(CH2)3-C(dO)-
60 (33)
a Isolated yields of chromatographically homogeneous materials, average
of two runs. The reactions were not optimized with respect to time. b E:Z
) 6:1 (1H NMR). c In the presence of finely ground 4 Å molecular sieves.
bromide 36 showed almost identical yields.16 Even though
there was no single catalyst that was the best for all three
substrates, some ligands such as IMes, Cy3P (Cy ) cyclo-
hexyl), and PtBu3 allowed good yields to be attained for the
(5) Recent examples: (a) Margolis, B. J.; Long, K. A.; Laird, D. L. T.;
Ruble, J. C.; Pulley, S. R. J. Org. Chem. 2007, 72, 2232. (b) Nagano, T.;
Kimoto, H.; Nakatsuji, H.; Motoyoshiya, J.; Aoyama, H.; Tanabe, Y.; Nishii,
Y. Chem. Lett. 2007, 36, 62. (c) Burns, M. J.; Fairlamb, I. J. S.; Kapdi,
A. R.; Sehnal, P.; Taylor, R. J. K. Org. Lett. 2007, 9, 5397. (d) Flackenstein,
C. A.; Plenio, H. Green Chem. 2007, 9, 1287. (e) Pomeisl, K.; Holy, A.;
Pohl, R. Tetrahedron Lett. 2007, 48, 3065. (f) Ruben, M.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 3844. (g) Billingsley, K.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 3358. (h) Conreaux, D.; Bossharth, E.;
Monteiro, N.; Besbordes, P.; Vors, J.-P.; Balme, G. Org. Lett. 2007, 9,
271. (i) Maerten, E.; Sauthier, M.; Morteux, A.; Castanet, Y. Tetrahedron
2007, 63, 682. (j) Pereira, R.; Furst, A.; Iglesias, B.; Germain, P.;
Gronemeyer, H.; de Lera, A. R. Org. Biomol. Chem. 2006, 4, 4514. (k)
Panatieri, R. B.; Reis, J. S.; Borges, L. P.; Nogueira, C. W.; Zeni, G. Synlett
2006, 3161. (l) Utas, J. E.; Olofson, B.; Aakermark, B. Synlett 2006, 1965.
(m) Romero, M.; Harrak, Y.; Basset, J.; Ginet, L.; Constans, P.; Pujol, M. D.
Tetrahedron 2006, 62, 9010. (n) Organ, M. G.; Avola, S.; Dubovyk, I.;
Hadei, N.; Kantchev, E. A. B.; O’Brien, C. J.; Valente, C. Chem.-Eur. J.
2006, 12, 4749. (o) Forgoine, P.; Brochu, M.-C.; St-Onge, M.; Thesen,
K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.
(p) Billingsley, K.; Anderson, K. W.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2006, 45, 3483. (q) Prediger, P.; Moro, A. V.; Nogueira, C. W.;
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2006, 71, 3786. (r) Denmark, S. E.; Baird, J. D. Org. Lett. 2006, 8, 793.
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39, 17. (b) Zapf, A.; Beller, M. Chem. Commun. 2005, 431.
(7) Reviews and books: (a) N-Heterocyclic Carbenes in Transition Metal
Catalysis; Glorius, F., Ed.; Springer-Verlag: Berlin Heildergerg, 2007. (b)
Kantchev, E. A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem., Int. Ed.
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Int. Ed. 2002, 41, 1290.
a
b
The reactions were not optimized with respect to time. The yield of
22 is based on the recovered starting bromide (49%).
(8) Reviews: (a) Dupont, J.; Consorti, C. S.; Spencer, J. Chem. ReV.
2005, 105, 2527. (b) Beletskaya, I. P.; Cheprakov, A. V. J. Organomet.
Chem. 2004, 689, 4055.
nylphosphonate (27), phenyl vinyl sulfone (28), and cyclo-
hexenone (29) mediated by NHC-Pd catalysts (products 31,
61%; 32, 37%; and 33, 60%, respectively).
(9) (a) Lebel, H.; Janes, M. K.; Charette, A. B.; Nolan, S. P. J. Am.
Chem. Soc. 2004, 126, 5046. (b) Selvakumar, K.; Zapf, A.; Spannenberg,
A.; Beller, M. Chem.-Eur. J. 2002, 8, 3901. (c) Yang, C.; Nolan, S. P.
Synlett 2001, 1539.
A comparison of the catalytic activity of complex 3 and a
total of 14 Heck-Mizoroki precatalysts15 revealed some
interesting observations. (i) The catalysts were tested against
a panel of three “challenges” s “steric” (34), “electronic”
(35), and “catalyst poison” (36). The bulky bromide 34 was
the most discriminating, whereas the imidazole-derived
(10) While this work was in progress, a similar complex was reported
independently: Cao, X.-H.; Zheng, Y.; Yu, H.-W.; Shi, J.-C. J. Coord. Chem.
2007, 60, 207.
(11) Pfeffer, M. Inorg. Synth. 1989, 26, 211.
(12) (a) Frey, G. D.; Schu¨tz, J.; Herdtweck, E.; Herrmann, W. A.
Organometallics 2005, 24, 4416. (b) Viciu, M. S.; Kelly, R. A., III; Stevens,
E. D.; Naud, F.; Studer, M.; Nolan, S. P. Org. Lett. 2003, 5, 1479.
Org. Lett., Vol. 10, No. 18, 2008
3951

three substrates (“privileged” or “universal” ligands).17 (ii)
Generally, the ligand activity increased in the order: ligan-
dless < phosphane < NHC at a ligand:Pd molar ratio of
1:1. However, phosphane catalysts with more than one
phosphane per Pd tended to have better overall performance
(Table 3, entries 11 and 12). In contrast, trans-(IMes)2PdCl2
was completely inactive.9a (iii) The composition of the Pd
source was as important as the ligand s the palladacycles
showed overall best performance in the Heck-Mizoroki
reaction regardless of the nature of the ligand. (iv) Among
the Pd precursors investigated, preformed, well-defined,
single-component precatalysts generally outperformed in situ
prepared “brews” from (pro)ligands and simple Pd salts. The
fact that two of the very active and versatile biarylphosphane
ligands developed by Buchwald’s group (43, 44) led to very
low yields under our protocol (entries 9 and 10, Table 3)
was a case in point.18
Table 3. Comparison of the Catalytic Activity of Complex 3
with Other Precatalysts (1 mol % Pd) in the Heck-Mizoroki
Couplings of Challenging Aryl Bromides 34-36 with tert-Butyl
Acrylate (5)a
entry
Pd catalyst (1 mol %)
9/34 (%) 14/35 (%) 21/36 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
IMes-Pd(dmba)Cl (3)
IMes-Pd(π-allyl)Cl (37)
[IMes-Pd(NQ)]2 (38)
Pd-PEPPSI-IMes (39)
IMes·HCl (1)/Pd(OAc)2
77/23
30/66
27/73
32/69
3.0/98
92/0.0
85/1.2
65/12
65/17
34/42
71/2.7
91/0.0
75/0.0
52/22
63/17
60/31
65/25
32/58
46/41
50/33
69/7.8
63/27
62/79
73/7.3
74/0.5
61/8.8
62/18
55/8.8
18/78
Cy3P-Pd(dmba)Cl (40)b 70/19
In conclusion, we have developed a novel NHC-pallada-
cycle as a rationally designed precatalyst (3) for the
Heck-Mizoroki reaction of challenging substrates with
respect to both catalytic performance and practicality. The
preparation of other NHC-palladacycles and their use as
catalysts in Pd-mediated transformations are underway.
Complex 42
[Pd(PtBu3)2]
DavePhos (43)/Pd(OAc)2 0.9/89
XPhos (44)/Pd(OAc)2
Ph3P-Pd(dmba)Cl (41)b 21/64
[Pd(PPh3)4]
[Pd(dmba)Cl]2
Pd(OAc)2 as PdEnCat 30 7.5/93
Pd/C (10 wt %) 0.5/89
29/57
80/19
0.0/100 0.0/100
62/13
43/25
78/4.6
52/33
35/60
93/2.2
5.7/87
Acknowledgment. This work was funded by the Institute
of Bioengineering and Nanotechnology (Biomedical Re-
search Council, Agency for Science, Technology and Re-
search (A*STAR), Singapore). We thank Prof. M. G. Organ
(York University, Canada) for the generous gift of the Pd-
PEPPSI-IMes complex and Geok-Kheng Tan (National
University of Singapore) for single crystal X-ray structural
analysis of complex 3.
a Conditions: K2CO3 (2 equiv), NMP, 140 °C, 18 h. The catalysts were
handled in air and added as freshly prepared, argon-degassed 0.05 M solution
in NMP unless insoluble or >5 mg was needed. b Prepared according to
the NHC-palladacycle synthesis protocol with slight modifications (Scheme
1). 40: 78% yield. 41: 98% yield.
Supporting Information Available: Synthetic procedures
and characterization data for compounds 3, 6, 7-24, 30-33,
(13) (a) Frey, G. D.; Schu¨tz, J.; Herrmann, W. A. J. Organomet. Chem.
2006, 691, 2403. (b) Bedford, R. B.; Betham, M.; Coles, S. J.; Frost, R. M.;
Hursthouse, M. B. Tetrahedron 2005, 61, 9663. (c) Hiraki, K.; Onishi, M.;
Sewaki, K.; Sugino, K. Bull. Chem. Soc. Jpn. 1978, 51, 2548.
(14) Kwok, T. J.; Virgilio, J. A. Org. Process Res. DeV. 2005, 9, 694.
(15) (a) For 37: Viciu, M. S.; Germaneau, R. F.; Nolan, S. P. Org. Lett.
2002, 4, 4053. (b) For 38: see ref 9b. (c) For 39: O’Brien, C. J.; Kantchev,
E. A. B.; Valente, C.; Hadei, N.; Chass, G. A.; Lough, A.; Hopkinson,
A. C.; Organ, M. G. Chem.-Eur. J. 2006, 12, 4743. (d) For 40 and 41:
Bedford, R. B.; Cazin, C. S. J.; Coles, S. J.; Gelbrich, T.; Horton, P. N.;
Hursthouse, M. B.; Light, M. E. Organometallics 2003, 22, 987. (e) For
[Pd(tBu3P)2]: Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989.
This catalyst rapidly degraded upon dissolution in NMP and had to be
weighed in as a solid. (f) For 42: Schnyder, A.; Ingolese, A. F.; Studer,
M.; Blaser, H.-U. Angew. Chem., Int. Ed. 2002, 41, 3668. (g) For 43, 44:
see ref 6a.
(16) N-Methylimidazole-Pd complexes are also catalytically active in
the Heck-Mizoroki reaction of bromoarenes at 1 mol % Pd. See: Haneda,
S.; Ueba, C.; Eda, K.; Hayashi, M. AdV. Synth. Catal. 2007, 349, 833.
(17) As an additional consideration, the price of Cy3P is much lower
than IMes·HCl. Complex 40 is, therefore, also an excellent choice as a
Heck-Mizoroki catalyst from a practical point of view: van der Schaaf,
P. A.; Kolly, R.; Tinkl, M. PCT Int. Appl. WO 2003013723 (2003).
(18) Ebran, J.-P.; Hansen, A. L.; Gogsig, T. M.; Skrydstrup, T. J. Am.
Chem. Soc. 2007, 129, 6931.
40, and 41 and crystallographic information file (.cif) for
complex 3. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL8012809
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Org. Lett., Vol. 10, No. 18, 2008